The present invention relates to controlled release unit dose formulations containing an antihyperglycemic drug. More specifically, the present invention relates to an oral dosage form comprising a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride or the metformin salts described in U.S. Pat. Nos. 3,957,853 and 4,080,472 which are incorporated herein by reference.
In the prior art, many techniques have been used to provide controlled and extended-release pharmaceutical dosage forms in order to maintain therapeutic serum levels of medicaments and to minimize the effects of missed doses of drugs caused by a lack of patient on compliance.
In the prior art are extended release tablets which have an osmotically active drug core surrounded by a semipermeable membrane. These tablets function by allowing a fluid such as gastric or intestinal fluid to permeate the coating membrane and dissolve the active ingredient so it can be released through a passageway in the coating membrane or if the active ingredient is insoluble in the permeating fluid, pushed through the passageway by an expanding agent such as a hydrogel. Some representative examples of these osmotic tablet systems can be found in U.S. Pat. Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407 and 4,783,337. U.S. Pat. No. 3,952,741 teaches an osmotic device wherein the active agent is released from a core surrounded by a semipermeable membrane only after sufficient pressure has developed within the membrane to burst or rupture the membrane at a weak portion of the membrane.
The basic osmotic device described in the above cited patents have been refined over time in an effort to provide greater control of the release of the active ingredient. For example U.S. Pat. Nos. 4,777,049 and 4,851,229 describe an osmotic dosage form comprising a semipermeable wall surrounding a core. The core contains an active ingredient and a modulating agent wherein the modulating agent causes the active ingredient to be released through a passageway in the semipermeable membrane in a pulsed manner. Further refinements have included modifications to the semipermeable membrane surrounding the active core such as varying the proportions of the components that form the membrane; i.e., U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625 or increasing the number of coatings surrounding the active core; i.e., U.S. Pat. Nos. 5,650,170 and 4,892,739.
Although vast amounts of research has been performed on controlled or sustained release compositions and in particular on osmotic dosage forms, very little research has been performed in the area of controlled or sustained release compositions that employ antihyperglycemic drugs.
Metformin is an oral antihyperglycemic drug used in the management of non-insulin-dependent diabetes mellitus (NIDDM). It is not chemically or pharmacologically related to oral sulfonylureas. Metformin improves glucose tolerance in NIDDM patients by lowering both basal and postprandial plasma glucose. Metformin hydrochloride is currently marketed as GLUCOPHAGE(copyright) tablets by Bristol-Myers Squibb Co. Each GLUCOPHAGE(copyright) tablet contains 500,850 or 1000 mg of metformin hydrochloride. There is no fixed dosage regimen for the management of hyperglycemia in diabetes mellitus with GLUCOPHAGE(copyright). Dosage of GLUCOPHAGE(copyright) is individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended dose of 2550 mg per day.
Metformin has been widely prescribed for lowering blood glucose in patients with NIDDM. However, being a short acting drug, metformin requires twice-daily (b.i.d.) or three-times-a-day (t.i.d.) dosing. Adverse events associated with metformin use are often gastrointestinal in nature (e.g., anorexia, nausea, vomiting and occasionally diarrhea, etc.). These adverse events may be partially avoided by either reducing the initial and/or maintenance dose or using an extended-release dosage form. Another clear advantage of an extended release dosage form is a reduction in the frequency of administration. All of these findings suggest that an extended-release dosage form of metformin may improve the quality of therapy in patients with NDDM and the safety profile relative to a conventional dosage form.
The limited work on controlled or sustained release formulations that employ antihyperglycemic drugs such as metformin hydrochloride includes the combination of the antihyperglycemic drug and an expanding or gelling agent to control the release of the drug from the dosage form. This research is exemplified by the teachings of WO 96/08243 and by the GLUCOPHAGE(copyright) metformin HCl product.
It is reported in the 50th Edition of the Physicians"" Desk Reference, copyright 1996, p. 753, that food decreases the extent and slightly delays the absorption of metformin delivered by the GLUCOPHAGE(copyright) dosage form. This decrease is shown by approximately a 40% lower peak concentration, a 25% lower bioavailability and a 35-minute prolongation of time to peak plasma concentration following administration of a single GLUCOPHAGE(copyright) tablet containing 850 mg of metformin HCl with food compared to the similar tablet administered under fasting conditions.
A controlled release metformin dosage form is also described in WO 99/47128. This reference describes a controlled release delivery system for metformin which includes an inner solid particulate phase formed of substantially uniform granules containing metformin and one or more hydrophilic polymers, one or more hydrophobic polymers and one or more hydrophobic materials, and an outer continuous phase in which the above granules are embedded and dispersed throughout. The outer continuous phase includes one or more hydrophilic polymers, one or more hydrophobic polymers and one or more hydrophobic materials.
Our own WO 99/47125 discloses controlled release metformin formulations providing a Tmax from 8 to 12 hours.
It is an object of the present invention to provide a controlled or sustained release of an antihyperglycemic drug which provides effective control of blood glucose levels in humans.
It is a further object of the present invention to provide a method of treating human patients with non-insulin-dependent diabetes mellitus (NIDDM) on a once-a-day basis with an antihyperglycemic drug which provides effective control of blood glucose levels in humans.
It is a further object of the present invention to provide formulations for treating human patients with non-insulin-dependent diabetes mellitus (NIDDM) which provides advantages over the state-of-the-art, and which may be administered on a once-a-day basis by itself or together with other antidiabetic agents, and methods thereof.
It is a further object of the present invention to provide a controlled or sustained release formulation of an antihyperglycemic drug wherein the bioavailability of the drug is not decreased by the presence of food.
It is a further object of the present invention to provide a controlled or sustained release formulation of an antihyperglycemic drug that does not employ an expanding polymer.
It is also a further object of the present invention to provide a controlled or sustained release formulation of an antihyperglycemic drug that can provide continuous and non-pulsating therapeutic levels of the drug to an animal or human in need of such treatment over a twelve hour to twenty-four hour period.
It is an additional object of other embodiments of the present invention to provide a controlled or sustained release formulation for an antihyperglycemic drug that obtains peak plasma levels from 5.5 to 7.5 hours after administration under various conditions. Alternatively, the time to peak plasma levels are from 6.0 to 7.0, from 5.5 to 7.0 or from 6.0 to 7.5.
It is also an object of this invention to provide a controlled or sustained release pharmaceutical formulation having a homogeneous core wherein the core component may be made using ordinary tablet compression techniques.
In accordance with the above-mentioned objects and others, the present invention provides a controlled release oral dosage form comprising an antihyperglycemic drug, preferably a biguanide (e.g., metformin or a pharmaceutically acceptable salt thereof) that is suitable for providing once-a-day administration of the drug, wherein the dosage form provides a mean time to maximum plasma concentration (Tmax) of the drug from 5.5 to 7.5 hours after administration. The dosage form comprises the drug and a membrane. In certain preferred embodiments, the dosage form comprises a tablet.
In preferred embodiments, the controlled release oral dosage form of the present invention is a tablet comprising:
(a) a core comprising:
(i) the antihyperglycemic drug;
(ii) optionally a binding agent; and
(iii) optionally an absorption enhancer;
(b) a membrane coating surrounding the core; and
(c) at least one passageway in the membrane.
When the drug is metformin or a pharmaceutically acceptable salt thereof and is administered on a once-a-day basis, the daily dose may vary, e.g., from about 500 mg to about 2500 mg. Such daily dose may be contained in one controlled-release dosage form of the invention, or may be contained in more than one such dosage form. For example, a controlled-release metformin dosage form may be formulated to contain about 1000 mg of the drug, and two of said dosage form may be administered together to provide once-a-day metformin therapy. The daily dose of the drug (i.e. metformin or pharmaceutically acceptable salt thereof) may range from about 500 mg to about 2500 mg, from about 1000 mg to about 2500 mg, or from about 2000 mg to about 2500 mg, depending on the clinical needs of the patient.
In certain preferred embodiments, the controlled release solid oral dosage form of the present invention provides a width at 50% of the height of a mean plasma concentration/time curve of the drug (e.g., of metformin) from about 4.5 to about 13 hours, more preferably from about 5.5 to about 10 hours, more preferably from about 6 to about 8 hours.
In certain embodiments, the controlled release oral dosage form of the present invention provides a mean maximum plasma concentration (Cmax) of the antihyperglycemic drug which is more than about seven times the mean plasma level of said drug at about 24 hours after administration. In preferred embodiments, the controlled release oral dosage form of the present invention provides a mean maximum plasma concentration (Cmax) of the drug which is from about 7 times to about 14 times the plasma level of the drug at about 24 hours after the administration, more preferably from about 8 times to about 12 times the plasma level of the drug at about 24 hours after administration.
In certain embodiments of the present invention, when the drug is metformin or a pharmaceutically acceptable salt thereof, the controlled release oral dosage form provides a mean maximum plasma concentration (Cmax) of the drug that is about 1500 ng/ml to about 3000 ng/ml, based on administration of a 2000 mg once-a-day dose of metformin, more preferably about 1700 ng/ml to about 2000 ng/ml, based on administration of a 2000 mg once-a-day dose of metformin.
In certain embodiments of the present invention, when the drug is metformin or a pharmaceutically acceptable salt thereof, the controlled release dosage form provides a mean AUC0-24hr that is about 17200 ng.hr/ml to about 33900 ng.hr/ml, based on administration of a 2000 mg once-a-day dose of metformin; preferably about 17200 ng.hr/ml to about 26500 ng.hr/ml, based on administration of a 2000 mg once-a-day dose of metformin; more preferably about 19800 ng.hr/ml to about 33900 ng.hr/ml, based on administration of a 2000 mg once-a-day dose of metformin.
In certain embodiments of the invention, the administration of the antihyperglycemic drug, e.g., at least one metformin dosage form provides a mean AUC0-24hr from at least 80%, preferably at least 90% of the mean AUC0-24 provided by administration of the reference standard (GLUCOPHAGE) twice a day, wherein the daily dose of the reference standard is equal to the once-a day dose of metformin administered in the controlled release oral dosage form of the present invention.
In certain embodiments of the present invention, the controlled release dosage form exhibits the following dissolution profiles of the antihyperglycemic drug (e.g., metformin) when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal gastric fluid (pH 7.5 phosphate buffer) at 37xc2x0 C.: 0-30% of the drug released after 2 hours; 10-45% of the drug released after 4 hours; 30-90% of the drug released after 8 hours; not less than 50% of the drug released after 12 hours; not less than 60% of the drug released after 16 hours; and not less than 70% of the drug released after 20 hours.
In certain preferred embodiments, the controlled release solid oral dosage form exhibits the following dissolution profiles when tested in USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal gastric fluid (pH 7.5 phosphate buffer) at 37xc2x0 C.: 0-25% of the drug (e.g., metformin or a pharmaceutically acceptable salt thereof) released after 2 hours; 20-40% of the drug released after 4 hours; 45-90% of the drug released after 8 hours; not less than 60% of the drug released after 12 h ours; not less than 70% of the drug released after 16 hours; and not less than 80% of the drug released after 20 hours.
With respect to embodiments of the present invention where the antihyperglycemic drug is metformin, it has been found that drugs such as metformin provide substantially linear pharmacokinetics up to a level of about 2 grams per day. Therefore, it is contemplated for purposes of the present invention that a given plasma level (e.g., Cmax) of metformin per specified dose will be directly proportional to other doses of metformin. Such proportional doses and plasma levels are contemplated to be within the scope of the invention and to be within the scope of the appended claims.
The dosage form of the present invention can provide therapeutic levels of the antihyperglycemic drug for twelve to twenty-four hour periods and does not exhibit a decrease in bioavailability if taken with food. In fact, a slight increase in the bioavailability of the antihyperglycemic drug is observed when the controlled release dosage form of the present invention is administered with food. In a preferred embodiment, the dosage form can be administered once-a-day, ideally with or after a meal, preferably with or after the evening meal, and provides therapeutic levels of the drug throughout the day with peak plasma levels being obtained between 5.5 to 7.5 hours after administration.
The present invention is also directed to a method of lowering blood glucose levels in human patients needing treatment for non-insulin-dependent diabetes mellitus (NIDDM), comprising orally administering to human patients on a once-a-day basis a dose of a drug comprising a biguanide (e.g., metformin or a pharmaceutically acceptable salt thereof), said drug being contained in at least one solid oral controlled release dosage form of the present invention. When the drug is metformin, the daily dose of the drug may be from about 500 mg to about 2500 mg, from about 1000 mg to about 2500 mg, or from about 2000 mg to about 2500 mg, depending on the clinical needs of the patient.
The controlled release dosage form of the present invention provides a delayed Tmax, as compared to the Tmax provided by GLUCOPHAGE. The delayed Tmax occurs from 5.5 to 7.5 hours after administration. If the drug (e.g., metformin) is administered at dinner time, the Tmax would occur during the time when gluconeogenesis is usually at its highest (e.g., around 2 am.).
The present invention also includes a method of treating patients with NIDDM comprising orally administering to human patients on a once-a-day basis a dose of a drug comprising a biguanide (e.g., metformin or a pharmaceutically acceptable salt thereof), contained in at least one oral controlled release dosage form of the present invention. When the drug is metformin, the daily dose of the drug may be from about 500 mg to about 2500 mg, from about 1000 mg to about 2500 mg, or from about 2000 mg to about 2500 mg, depending on the clinical needs of the patient. In certain embodiments, the method of treatment according to the present invention involves once-per-day metformin monotherapy as an adjunct to diet to lower blood glucose in patients with NIDDM whose hyperglycemia may not be satisfactorily managed on diet alone. In certain other embodiments, the once-a-day metformin therapy of the present invention may be used concomitantly with a sulfonylurea, e.g., when diet and monotherapy with a sulfonylurea alone do not result in adequate glycemic control. In certain other embodiments, the once-a-day metformin therapy of the present invention may be used concomitantly with a glitazone, e.g., when diet and monotherapy with a glitazone alone do not result in adequate glycemic control.
The present invention is further directed to a method of controlling the serum glucose concentration in human patients with NIDDM, comprising administering to patients having NIDDM on a once-a-day basis, preferably at dinner time, an effective dose of a biguanide (e.g., metformin) contained in at least one oral controlled release dosage form of the present invention.
The present invention further includes a controlled-release dosage form of a drug comprising a biguanide (e.g., metformin) suitable for once-a-day administration to human patients with NIDDM, the dosage form comprising an effective amount of the drug to control blood glucose levels for up to about 24 hours and an effective amount of a controlled-release carrier to provide controlled release of the drug with a mean time to maximum plasma concentration (Tmax) of the drug from 5.5 to 7.5 hours after administration and a width at 50% of the height of a mean plasma concentration/time curve of the drug from about 6 to about 13 hours.
In preferred embodiments, the administration of the controlled-release dosage form occurs at fed state, more preferably at dinner time.
In certain preferred embodiments, the controlled-release dose of the drug (e.g., metformin or a pharmaceutically acceptable salt thereof) according to the present invention is provided by one or more of a controlled-release tablet comprising
(a) a core comprising:
(i) the antihyperglycemic drug (e.g., metformin or a pharmaceutically acceptable salt thereof);
(ii) optionally a binding agent; and
(iii) optionally an absorption enhancer,
(b) a membrane coating surrounding the core; and
(c) at least one passageway in the membrane.
In certain preferred embodiments, the mean time to maximum plasma concentration of the drug is reached from 6.5 to 7.5 hours after administration at dinner time.
In certain embodiments of the invention when the drug is a biguanide (e.g. metformin or a pharmaceutically acceptable salt thereof), the controlled release dosage form provides upon single administration, a higher mean fluctuation index in the plasma than an equivalent dose of an immediate release composition administered as two equal divided doses, one divided dose at the start of the dosing interval and the other divided dose administered 12 h ours later, preferably maintaining bioavailability from at least 80% preferably from at least 90% of the immediate release composition.
In certain embodiments of the present invention, the mean fluctuation index of the dosage form is from about 1 to about 4, preferably about 2 to about 3, more preferably about 2.5.
In certain embodiments of the invention which exhibit a higher mean fluctuation index in the plasma than an equivalent dose of an immediate release composition administered as two equal divided doses, the ratio of the mean fluctuation index between the dosage form and the immediate release composition is about 3:1, preferably about 2:1, more preferably 1.5:1.
When the drug is metformin or a pharmaceutically acceptable salt thereof, the doses of drug which exhibit the above disclosed mean fluctuation indexes can be any effective dose administered to a patient with NIDDM for the reduction of serum glucose levels. For example, the dose can from about 500 mg to about 2500 mg, from about 200 mg to about 2000 mg or from about 850 mg to about 1700 mg metformin or pharmaceutically acceptable salt thereof.
The drugs which may used in conjunction with the present invention include those drugs which are useful for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), including but not limited to biguinides such as metformin or buformin or pharmaceutically acceptable salts thereof. When the drug used in the present invention is metformin, it is preferred that the metformin be present in a salt form, preferably as metformin hydrochloride.
The term xe2x80x9cmetforminxe2x80x9d as it is used herein means metformin base or any pharmaceutically if acceptable salt e.g., metformin hydrochloride.
The term xe2x80x9cdosage formxe2x80x9d as it is used herein means at least one unit dosage form of the present invention (e.g. the daily dose of the antihyperglycemic agent can be contained in 2 unit dosage forms of the present invention for single once-a-day administration).
The term xe2x80x9cmorningxe2x80x9d as it is used herein with respect to the dosing of the controlled release formulations of the invention means that the controlled release formulation is orally administered early in the day after the patient has awakened from overnight sleep, generally between about 6 a.m. and 11 a.m. (regardless of whether breakfast is eaten at that time, unless so specified herein).
The term xe2x80x9cdinnertimexe2x80x9d or xe2x80x9cat dinnerxe2x80x9d as it is used herein with respect to the dosing of the controlled release formulations of the invention means that the controlled release formulation is orally administered at a time when dinner is normally eaten (regardless of whether a meal is actually eaten at that time, unless so specified herein), generally between about 4 p.m. and 8 p.m.
The term xe2x80x9cbedtimexe2x80x9d as it is used herein with respect to the dosing of the controlled release formulations of the invention means that the controlled release formulation is orally administered before the patient goes to bed in the evening, generally between about 8 p.m. and 12 p.m.
The term xe2x80x9ctherapeutically effective reductionxe2x80x9d when used herein is meant to signify that blood glucose levels are reduced by approximately the same amount as an immediate release reference standard (e.g., GLUCOPHAGE(trademark)) or more, when the controlled release dosage form is orally administered to a human patient on a once-a-day basis.
The term xe2x80x9csustained releasexe2x80x9d and xe2x80x9ccontrolled releasexe2x80x9d are used interchangeably in this application and are defined for purposes of the present invention as the release of the drug from the dosage form at such a rate that when a once-a-day dose of the drug is administered in the sustained release or controlled-release form, blood (e.g., plasma) concentrations (levels) of the drug are maintained within the therapeutic range but below toxic levels over a period of time from about 12 to about 24 hours. When the drug used in the present invention is metformin (preferably metformin hydrochloride) the controlled release solid oral dosage form containing such drug is also referred to as xe2x80x9cMetformin XT.xe2x80x9d
The term xe2x80x9cCmaxxe2x80x9d is the highest plasma concentration of the drug attained within the dosing interval, i.e., about 24 hours.
The term xe2x80x9cCminxe2x80x9d is the minimum plasma concentration of the drug attained within the dosing interval, i.e. about 24 hours.
The term xe2x80x9cCavgxe2x80x9d as used herein, means the plasma concentration of the drug within the dosing interval, i.e. about 24-hours, and is calculated as AUC/dosing interval.
The term xe2x80x9cTmaxxe2x80x9d is the time period which elapses after administration of the dosage form at which the plasma concentration of the drug attains the highest plasma concentration of drug attained within the dosing interval ( i.e., about 24 hours).
The term xe2x80x9cAUCxe2x80x9d as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete 24-hour interval.
The term xe2x80x9csteady statexe2x80x9d means that the blood plasma concentration curve for a given drug does not substantially fluctuate after repeated doses to dose of the formulation.
The term xe2x80x9csingle dosexe2x80x9d means that the human patient has received a single dose of the drug formulation and the drug plasma concentration has not achieved steady state.
The term xe2x80x9cmultiple dosexe2x80x9d means that the human patient has received at least two doses of the drug formulation in accordance with the dosing interval for that formulation (e.g., on a once-a-day basis). Patients who have received multiple doses of the controlled release formulations of the invention may or may not have attained steady state drug plasma levels, as the term multiple dose is defined herein.
The term xe2x80x9ca patientxe2x80x9d means that the discussion (or claim) is directed to the pharmacokinetic parameters of an individual patient and/or the mean pharmacokinetic values obtained from a population of patients, unless further specified.
The term xe2x80x9cmeanxe2x80x9d, when preceding a pharmacokinetic value (e.g. mean Tmax) represents the arithmetic mean value of the pharmacokinetic value taken from a population of patients unless otherwise specified (e.g. geometric mean).
The term xe2x80x9cDegree of Fluctuationxe2x80x9d is expressed as (Cmaxxe2x88x92Cmin)/Cavg.